The overall goal of this project is to define the molecular events involved in the transformation of low-grade lymphomas to more aggressive forms. As a first approach, we have studied a series of recurrent follicular lymphomas to assess the status of their immunoglobulin and bcl-2 restriction patterns over time. We have found that immunoglobulin gene restriction pattern changes occur frequently (30% of the cases studied). Changes in the bcl-2 gene restriction fragments were not observed. We believe the changes in the immunoglobulin genes may be due to the normal physiologic "mutator" function which gives rise to somatic mutation in B cell development. If a cell containing a mutation at a restriction enzyme site undergoes a second genetic event that imparts a growth advantage, the first mutation will become detectable as a restriction pattern change. In this way, changes in the immunoglobulin genes may serve as a marker for subsequent growth promoting mutations. We have begun to investigate potential second events which could impart a selective growth advantage to a lymphoma cell or result in aggressive transformation of a lymphoma. To this end, we are currently analyzing the potential role of several oncogenes and anti-oncogenes. We have found retinoblastoma gene abnormalities at the DNA and RNA levels in several different types of lymphomas and are currently attempting to extend these findings by studying expression at the protein level in a collaborative effort with Dr. William Benedict. We have also surveyed a large series of lymphomas with probes for several other genetic loci associated with disease progression and/or high grade histology (BCL-3, BCL-4), but have found only sporadic involvement of these other loci.